The long term goal of the proposed research is to understand aging-associated changes in autoantibody formation and humoral responses to vaccination. In the current period of this grant support, we have confirmed the increased frequency of autoantibody production, identified changes in the expressed Ig gene repertoire in human aging, and found a high degree of variability among elderly humans in frequency of Ig gene mutations and in the memory B cell numbers. We will pursue the implications of these findings, both in continuing studies on the origins of aging-associated autoantibodies and in tests of the functional significance of variations in memory B cell numbers. Specific Aim 1. We will continue to test alternate hypotheses for mechanisms underlying autoantibody formation, to distinguish between unmasked expression of natural autoantibodies and autoantigen-stimulated selection. Specific Aim 2: We will test the hypothesis that marked deviations from normal numbers of CD27+ memory B cells predict a poor response of nursing home residents to influenza vaccination and that their memory B cell changes are related to underlying changes in T cell functions. We will determine: a. whether CD19+CD27+ cells correspond to memory B cells, with mutated V region genes, in elderly people as in young adults; b. whether the size of the CD27+ memory B cell population is a fixed characteristic for individuals, or a labile parameter that may reflect disease or diminished regulation; c. whether influenza-specific memory B cells are present among the CD27+ B cells of vaccinated subjects; d. Whether unusually low or high levels of CD27+ B cells are correlated with unusual levels of T cell subset populations and/or low T cell function, which might underlie B cell dysregulation; and e. whether nursing home residents with either very low or very high numbers of memory B cells generate a low humoral response to influenza vaccine.